DESCRIPTION Abstract: Imagine calling T-cells, macrophages, and antibodies into action by taking a simple pill that instantaneously programs both adaptive and innate arms of the immune system to attack a tumor or virus, preventing infection and halting disease. Such an approach could meet major unmet challenges in biomedical research and therapy. My goal is to develop novel approaches that allow innate and acquired immunity to be purposefully targeted to pathogens of interest. These studies build on recently revealed mechanisms of Toll-like receptor signaling, ideas concerning approaches of targeting their sensing abilities to pathogens of defined interest and insights gained from our own invention of chemically programmed antibodies. Ultimately, these studies will allow scientists to program a variety of immune cells and responses to attack pathogens of interest using a variety of mechanisms. We will apply these results to studies in cancer therapy. Furthermore, we will explore novel approaches that should allow for circulating immunoglobulins induced with covalent vaccines to be programmed to inhibit HIV-1 and flu virus entry. The vaccines that result from these studies may be of both prophylactic and therapeutics utility. I will develop novel chemical approaches aimed at learning how to purposefully target innate immunity, T- cells, and macrophages to defined pathogens. I will apply these developments to create new cancer therapies. I will develop a novel approach to orally available chemically programmed immunity. I will apply developments in orally available chemically programmed immunity towards new vaccine strategies for HIV-1 and flu.